[3][4] Because of the unique phrasing of the song's title, "25 or 6 to 4" has been interpreted to mean everything from a quantity of illicit drugs to the name of a famous person in code.

The most common variant of it goes from A minor to G to F sharp to F to E, although it can also be played as Am-G-D-F-E or even Am-G-D9-F♯-F-E...[7]Hermann details the riff's similarity to the chord progression in Led Zeppelin's version of "Babe I'm Gonna Leave You" by Anne Bredon, which came out a year before "25 or 6 to 4", and the similarity of that chord progression to one in George Harrison's song "While My Guitar Gently Weeps", which came out even earlier.

[7] The original recording features an electric guitar solo using a wah-wah pedal by Chicago guitarist Terry Kath, and a lead vocal line in the Aeolian mode.

[8] According to the recollections of producer James William Guercio and horn player Lee Loughnane, Cetera had to record the vocal while his jaw was still wired together after he had been attacked at a baseball game at Dodger Stadium on May 20, 1969.

[18] An updated version of "25 or 6 to 4" was recorded for the 1986 album Chicago 18 with James Pankow listed as co-writer,[19] and new band member Jason Scheff on lead vocals.

[25][26][27] In 2016, the group's former drummer Danny Seraphine reunited on stage with Chicago to perform "25 or 6 to 4" and two other songs at their induction ceremony for the Rock and Roll Hall of Fame.

The song has been covered by various artists, including Straitjacket, Local H, Intruder,[44] Bruce Foxton,[45] The Moog Cookbook,[46] Earth, Wind & Fire, Paul Gilbert, Pacifika,[47] Mötley Crüe lead singer Vince Neil,[48] Umphrey's McGee,[49] Nick Ingman,[50] and as an instrumental on the Dave Koz collaboration album Summer Horns.

It appears as an on-disc track in the video game Rock Band 3;[57] has been featured on the animated TV series King of the Hill's season 11 episode, "Luanne Gets Lucky";[58][59] and was used in the 2017 film I, Tonya, directed by Craig Gillespie and starring Margot Robbie and Sebastian Stan.

[63] Paul Gilbert, former guitarist of Racer X and Mr. Big, says that a "really primitive version" of "25 or 6 to 4" was one of the first songs he taught himself to play on the guitar, using one string.